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Disease-associated oligodendrocyte signatures are spatiotemporally dysregulated in spinocerebellar ataxia type 3

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by a CAG repeat expansion in the ATXN3 gene. Though the ATXN3 protein is expressed ubiquitously throughout the CNS, regional pathology in SCA3 patients is observed within select neuronal populations and more recently within o...

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Autores principales: Schuster, Kristen H., DiFranco, Danielle M., Putka, Alexandra F., Mato, Juan P., Jarrah, Sabrina I., Stec, Nicholas R., Sundararajan, Vikram O., McLoughlin, Hayley S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9975394/
https://www.ncbi.nlm.nih.gov/pubmed/36875652
http://dx.doi.org/10.3389/fnins.2023.1118429
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author Schuster, Kristen H.
DiFranco, Danielle M.
Putka, Alexandra F.
Mato, Juan P.
Jarrah, Sabrina I.
Stec, Nicholas R.
Sundararajan, Vikram O.
McLoughlin, Hayley S.
author_facet Schuster, Kristen H.
DiFranco, Danielle M.
Putka, Alexandra F.
Mato, Juan P.
Jarrah, Sabrina I.
Stec, Nicholas R.
Sundararajan, Vikram O.
McLoughlin, Hayley S.
author_sort Schuster, Kristen H.
collection PubMed
description Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by a CAG repeat expansion in the ATXN3 gene. Though the ATXN3 protein is expressed ubiquitously throughout the CNS, regional pathology in SCA3 patients is observed within select neuronal populations and more recently within oligodendrocyte-rich white matter tracts. We have previously recapitulated these white matter abnormalities in an overexpression mouse model of SCA3 and demonstrated that oligodendrocyte maturation impairments are one of the earliest and most progressive changes in SCA3 pathogenesis. Disease-associated oligodendrocyte signatures have recently emerged as significant contributors to several other neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, but their role in regional vulnerability and disease progression remains unexplored. Here, we are the first to comparatively assess myelination in human tissue in a region-dependent manner. Translating these findings to SCA3 mouse models of disease, we confirmed endogenous expression of mutant Atxn3 leads to regional transcriptional dysregulation of oligodendrocyte maturation markers in Knock-In models of SCA3. We then investigated the spatiotemporal progression of mature oligodendrocyte transcriptional dysregulation in an overexpression SCA3 mouse model and how it relates to the onset of motor impairment. We further determined that regional reduction in mature oligodendrocyte cell counts in SCA3 mice over time parallels the onset and progression of brain atrophy in SCA3 patients. This work emphasizes the prospective contributions of disease-associated oligodendrocyte signatures to regional vulnerability and could inform timepoints and target regions imperative for biomarker assessment and therapeutic intervention in several neurodegenerative diseases.
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spelling pubmed-99753942023-03-02 Disease-associated oligodendrocyte signatures are spatiotemporally dysregulated in spinocerebellar ataxia type 3 Schuster, Kristen H. DiFranco, Danielle M. Putka, Alexandra F. Mato, Juan P. Jarrah, Sabrina I. Stec, Nicholas R. Sundararajan, Vikram O. McLoughlin, Hayley S. Front Neurosci Neuroscience Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by a CAG repeat expansion in the ATXN3 gene. Though the ATXN3 protein is expressed ubiquitously throughout the CNS, regional pathology in SCA3 patients is observed within select neuronal populations and more recently within oligodendrocyte-rich white matter tracts. We have previously recapitulated these white matter abnormalities in an overexpression mouse model of SCA3 and demonstrated that oligodendrocyte maturation impairments are one of the earliest and most progressive changes in SCA3 pathogenesis. Disease-associated oligodendrocyte signatures have recently emerged as significant contributors to several other neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, but their role in regional vulnerability and disease progression remains unexplored. Here, we are the first to comparatively assess myelination in human tissue in a region-dependent manner. Translating these findings to SCA3 mouse models of disease, we confirmed endogenous expression of mutant Atxn3 leads to regional transcriptional dysregulation of oligodendrocyte maturation markers in Knock-In models of SCA3. We then investigated the spatiotemporal progression of mature oligodendrocyte transcriptional dysregulation in an overexpression SCA3 mouse model and how it relates to the onset of motor impairment. We further determined that regional reduction in mature oligodendrocyte cell counts in SCA3 mice over time parallels the onset and progression of brain atrophy in SCA3 patients. This work emphasizes the prospective contributions of disease-associated oligodendrocyte signatures to regional vulnerability and could inform timepoints and target regions imperative for biomarker assessment and therapeutic intervention in several neurodegenerative diseases. Frontiers Media S.A. 2023-02-15 /pmc/articles/PMC9975394/ /pubmed/36875652 http://dx.doi.org/10.3389/fnins.2023.1118429 Text en Copyright © 2023 Schuster, DiFranco, Putka, Mato, Jarrah, Stec, Sundararajan and McLoughlin. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Schuster, Kristen H.
DiFranco, Danielle M.
Putka, Alexandra F.
Mato, Juan P.
Jarrah, Sabrina I.
Stec, Nicholas R.
Sundararajan, Vikram O.
McLoughlin, Hayley S.
Disease-associated oligodendrocyte signatures are spatiotemporally dysregulated in spinocerebellar ataxia type 3
title Disease-associated oligodendrocyte signatures are spatiotemporally dysregulated in spinocerebellar ataxia type 3
title_full Disease-associated oligodendrocyte signatures are spatiotemporally dysregulated in spinocerebellar ataxia type 3
title_fullStr Disease-associated oligodendrocyte signatures are spatiotemporally dysregulated in spinocerebellar ataxia type 3
title_full_unstemmed Disease-associated oligodendrocyte signatures are spatiotemporally dysregulated in spinocerebellar ataxia type 3
title_short Disease-associated oligodendrocyte signatures are spatiotemporally dysregulated in spinocerebellar ataxia type 3
title_sort disease-associated oligodendrocyte signatures are spatiotemporally dysregulated in spinocerebellar ataxia type 3
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9975394/
https://www.ncbi.nlm.nih.gov/pubmed/36875652
http://dx.doi.org/10.3389/fnins.2023.1118429
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